The respiratory tract faces unique immunologic demands. Since excessive immune or inflammatory responses can be as damaging to the lung as uncontrolled infection, it is thought that the respiratory tract has developed mechanisms that keep the pulmonary immune system and the associated inflammatory response in check, yet prepared to respond quickly to potentially deadly or disease-causing materials. Understanding these mechanisms is important for developing knowledge-based approaches to intervene in many pulmonary diseases. In order to separate those aspects of respiratory immunity that are determined locally from those that are determined at systemic sites, we examined respiratory immune responses in mice that lacked all encapsulated lymph nodes (LNs), Peyer?s patches and spleen, but retained the nasal associated lymphoid tissue (NALT), as well as the interstitial lymphoid areas of the lung. Using these mice, we demonstrated that the respiratory tract can perform many immune functions in the complete absence of conventional lymphoid organs. Furthermore, we showed that the NALT and the lymphoid areas of the lung are formed by mechanisms that bypass the lymphotoxin-a signaling pathway, which is required for the development of all encapsulated lymphoid organs. In light of our preliminary data, we hypothesize that respiratory immune responses can be initiated directly in the respiratory tract by novel mechanisms and that these mechanisms regulate respiratory immunity and accommodate the special needs of the respiratory system. To test this hypothesis, we propose to define in Aim 1 whether immune responses generated directly in the NALT and/or lung result in effective immunity to primary or secondary challenge, to determine in Aim 2 whether cellular immune responses generated in the NALT and/or lung differ in the absence of conventional lymphoid tissues, to determine in Aim 3 how humoral immune responses in the respiratory tract differ in the absence of conventional lymphoid tissues, and to determine in Aim 4 the molecular mechanisms that control the recruitment and organization of naive lymphocytes in the lung. Together, these experiments will clarify the immune functions of NALT as well as the interstitial lymphoid areas in the lung, and will identify those aspects of respiratory immunity that are specific to these tissues. The knowledge gained by these experiments will facilitate the rational design of protective or therapeutic strategies targeted to these tissues to control pulmonary diseases.